Vagus Nerve Neurostimulator With Multiple Patient-Selectable Modes For Treating Chronic Cardiac Dysfunction

ABSTRACT

A vagus nerve neurostimulator system with multiple patient-selectable modes for treating chronic cardiac dysfunction is provided. An implantable neurostimulator includes a pulse generator coupled to a therapy lead terminated by a pair of helical electrodes positioned over a cervical vagus nerve. The pulse generator is configured to deliver through the helical electrodes continuously-cycling, intermittent and periodic electrical stimulation that is parametrically defined to bi-directionally propagate through nerve fibers in the cervical vagus nerve. The implantable neurostimulator includes a magnetic switch configured to switch the pulse generator between a plurality of operating modes that are each separately selectable in response to a unique and remotely-applied magnetic signal. An external controller includes patient-actuatable controls configured to enable selection of one of the operating modes of the pulse generator. The external controller includes an electromagnetic transmitter configured to output the magnetic signal uniquely associated with the operating mode as selected with the controls.

FIELD

This application relates in general to chronic cardiac dysfunction therapy and, in particular, to a vagus nerve neurostimulator with multiple patient-selectable modes for treating chronic cardiac dysfunction.

BACKGROUND

Congestive heart failure (CHF) is a progressive and physically debilitating chronic medical condition in which the heart is unable to supply sufficient blood flow to meet the body's needs as a result of cardiovascular disease. CHF is a particular form of chronic cardiac dysfunction that affects nearly six million people each year in the United States alone and continues to be the leading cause of hospitalization for persons over the age of 65. Throughout the developed world, the number of people afflicted with symptomatic CHF exceeds 23 million.

CHF exacts a devastating toll on humanity. Symptoms stemming from CHF impact not only the individuals afflicted, but also care providers within their families. Without proper treatment, people with CHF will experience significantly increased morbidity and mortality. In the early stages of CHF, patients experience exercise intolerance and fatigue. In later stages, fluid accumulates in the peripheral limbs, gut and in the lungs. Hypoperfusion of vital organ systems causes chronic damage and leads to increased risk of multiple organ system failure and cardiac arrhythmia. The mortality rate of patients diagnosed with CHF in the first year following diagnosis is about 20%, while, on average, the mortality at five years is a staggering 50%. CHF is a serious, progressive condition that requires timely medical attention with a continuous, multifaceted therapeutic approach involving special drugs, interventional devices and chronically-implanted devices, as well as regular, periodic clinical monitoring by healthcare professionals trained to prescribe and manage care programs specifically tailored for patients suffering from CHF.

Pathologically, CHF is characterized by an elevated neuroexitatory state that is accompanied by impaired arterial and cardiopulmonary baroreflex function and reduced vagal activity. CHF is initiated by cardiac dysfunction, which triggers compensatory activations of the sympathoadrenal (sympathetic) nervous and the renin-angiotensin-aldosterone hormonal systems. Initially, these two mechanisms help the heart to compensate for deteriorating pumping function. Over time, however, overdriven sympathetic activation and increased heart rate promote progressive left ventricular dysfunction and remodeling, and ultimately foretell poor long term patient outcome.

Anatomically, the heart is innervated by sympathetic and parasympathetic nerves originating through the vagus nerve and arising from the body's cervical and upper thoracic regions. The sympathetic and parasympathetic nervous systems, though separate aspects of the autonomous nervous system, dynamically interact thorough signals partially modulated by cAMP and cGMP secondary messengers. When in balance, each nervous system can presynaptically inhibit the activation of the other nervous system's nerve traffic through these messengers. During CHF, the body suffers an autonomic imbalance of these two nervous systems, which leads to cardiac arrhythmogenesis, progressively worsening cardiac function, potential onset of comorbidities, and eventual death.

Currently, the standard of care for managing chronic cardiac dysfunction due to cardiovascular disease includes prescribing medication, such as diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, and mandating dietary and lifestyle changes. However, the effectiveness of these measures is palliative, not curative and patients often suffer side effects and comorbidities, such as pulmonary edema, sleep apnea, and myocardial ischemia. Re-titration of drug therapy following crisis may be required, and continued drug efficacy is not assured.

More recently, cardiac resynchronization therapy (CRT) has become available to patients presenting with impairment of systolic function, such as caused by an intraventricular conduction delay or bundle-branch block that forces the heart's ventricles to contract dyssynchronously. Typically, implantable CRT devices use a set of biventricular leads to stimulate both the ventricular septum and the lateral wall of the left ventricle. CRT restores the synchronous heartbeat through coordinated pacing of both ventricles and thereby improves the contractile performance of the heart. However, CRT is only helpful for treating systolic dysfunction and is not indicated for patients presenting with preserved ejection fraction. CRT is thus limited to only those patients exhibiting a wide QRS complex (mechanical dyssynchrony) and reduced left ventricular ejection fraction.

Medication and CRT are only partial solutions and neural stimulation has been proposed as a complimentary form of therapy for the treatment of chronic cardiac dysfunction, such as CHF, by addressing the underlying imbalance within the autonomic nervous system. The autonomic nervous system is composed of the sympathetic nervous system and the parasympathetic nervous system. Activity within and among elements of both sympathetic and parasympathetic systems serve to regulate cardiovascular function by exerting high resolution control of important biological processes mediated by ionic currents flowing across cell membranes. Cumulatively, the autonomic regulation of these biological processes results in homeostasis of heart rate and contractile performance. However, when disease processes derange autonomic function, homeostasis is lost and cardiovascular function is degraded; contractile performance becomes suboptimal and heart rate modulation becomes distorted in ways that create a positive feedback loop promoting progression of chronic cardiac dysfunction. The heart contains an intrinsic nervous system that includes spatially-distributed sensory afferent neurons, interconnecting local circuit neurons, and motor adrenergic and cholinergic efferent neurons. Peripheral cell stations of these neurons activate under the tonic influence of spinal cord and medullary reflexes and circulating catecholamines to influence spatially-overlapping regions of the heart. Suppression of excessive neural activation by electrically modulating select vagal nerve fibers through neural stimulation may help improve cardiac mechanical function and reduce the heart's intrinsic nervous system's propensity to induce atrial and ventricular arrhythmias during sudden or prolonged periods of arrhythmias during autonomic imbalance.

Currently, vagus nerve stimulation (VNS) is used clinically for the treatment of drug-refractory epilepsy and depression. VNS has been proposed as a long-term therapy for the treatment of CHF, such as described in Sabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,” Heart Fail. Rev., 16:171-178 (2011), the disclosure of which is incorporated by reference. The Sabbah paper discusses canine studies using a vagus stimulation device, manufactured by BioControl Medical Ltd., Yehud, Israel, which includes a signal generator, right ventricular endocardial sensing lead, and right vagus nerve cuff stimulation lead. The sensing leads enable stimulation of the right vagus nerve to be synchronized to the cardiac cycle through closed-loop feedback heart rate control. A bipolar nerve cuff electrode was surgically implanted on the right vagus nerve at the mid-cervical position. Electrical stimulation of the right cervical vagus nerve was delivered only when heart rate (beats per minute) increased beyond a preset threshold. Stimulation was provided at an impulse rate and intensity intended to reduce basal heart rate by ten percent by preferential stimulation of efferent vagal nerve fibers leading to the heart while blocking afferent neural impulses to the brain. Specifically, an asymmetric bi-polar multi-contact cuff electrode was employed to provide cathodic induction of action potentials while simultaneously applying asymmetric anodal blocks that were expected to lead to preferential, but not exclusive, activation of vagal efferent fibers. Although effective in restoring baroreflex sensitivity and, in the canine model, significantly increasing left ventricular ejection fraction and decreasing left ventricular end diastolic and end systolic volumes, restoration of autonomic balance was left unaddressed.

Other uses of electrical nerve stimulation for therapeutic treatment of various physiological conditions are described. For instance, U.S. Pat. No. 6,600,954, issued Jul. 29, 2003 to Cohen et al. discloses a method and apparatus for selective control of nerve fibers. An electrode device is applied to a nerve bundle capable of generating, upon activation, unidirectional action potentials to be propagated through both small diameter and large diameter sensory fibers in the nerve bundle, and away from the central nervous system. The device is particularly useful for reducing pain sensations in the legs and arms.

U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. discloses an apparatus for treatment of disorders by unidirectional nerve stimulation. An apparatus for treating a specific condition includes a set of one or more electrode devices that are applied to selected sites of the central or peripheral nervous system of the patient. For some applications, a signal is applied to a nerve, such as the vagus nerve, to stimulate efferent fibers and treat motility disorders, or to a portion of the vagus nerve innervating the stomach to produce a sensation of satiety or hunger. For other applications, a signal is applied to the vagus nerve to modulate electrical activity in the brain and rouse a comatose patient, or to treat epilepsy and involuntary movement disorders.

U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. discloses stimulation of autonomic nerves. An autonomic nerve is stimulated to affect cardiac function using a stimulation device in electrical communication with the heart by way of three leads suitable for delivering multi-chamber stimulation and shock therapy. In addition, the device includes a fourth lead having three electrodes positioned in or near the heart, or near an autonomic nerve remote from the heart. Power is delivered to the electrodes at a set power level. The power is delivered at a reduced level if cardiac function was affected.

U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk discloses terminating ventricular tachycardia. Cardioversion stimulation is delivered upon detecting a ventricular tachycardia. A stimulation pulse is delivered to a lead having one or more electrodes positioned proximate to a parasympathetic pathway. Optionally, the stimulation pulse is delivered post inspiration or during a refractory period to cause a release of acetylcholine.

U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagal stimulation for improving cardiac function in heart failure or CHF patients. An autonomic nerve is stimulated to affect cardiac function using a stimulation device in electrical communication with the heart by way of three leads suitable for delivering multi-chamber stimulation and shock therapy. In addition, the device includes a fourth lead having three electrodes positioned in or near the heart, or near an autonomic nerve remote from the heart. A need for increased cardiac output is detected and a stimulation pulse is delivered through an electrode, for example, proximate to the left vagosympathetic trunk or branch to thereby stimulate a parasympathetic nerve. If the stimulation has caused sufficient increase in cardiac output, ventricular pacing may then be initiated at an appropriate reduced rate.

U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. discloses nerve branch-specific action potential activation, inhibition and monitoring. Two preferably unidirectional electrode configurations flank a nerve junction from which a preselected nerve branch issues, proximally and distally to the junction, with respect to the brain. Selective nerve branch stimulation can be used in conjunction with nerve-branch specific stimulation to achieve selective stimulation of a specific range of fiber diameters, substantially restricted to a preselected nerve branch, including heart rate control, where activating only the vagal B nerve fibers in the heart, and not vagal A nerve fibers that innervate other muscles, can be desirous.

U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. discloses selective nerve fiber stimulation for treating heart conditions. An electrode device is adapted to be coupled to a vagus nerve of a subject and a control unit drives the electrode device by applying stimulating and inhibiting currents to the vagus nerve, which are capable of respectively inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers in the vagus nerve and inhibiting action potentials in the therapeutic direction in the second set of nerve fibers only. The nerve fibers in the second set have larger diameters than the nerve fibers in the first set. The control unit typically drives the electrode device to apply signals to the vagus nerve to induce the propagation of efferent action potentials towards the heart and suppress artificially-induced afferent action potentials toward the brain. Patient control is not mentioned.

U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat. No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiac threshold vagal nerve stimulation. A vagal nerve stimulator is configured to generate electrical pulses below a cardiac threshold, which are transmitted to a vagal nerve, so as to inhibit or reduce injury resulting from ischemia. The cardiac threshold is a threshold for energy delivered to the heart above which there is a slowing of the heart rate or conduction velocity. In operation, the vagal nerve stimulator generates the electrical pulses below the cardiac threshold, such that heart rate is not affected. Patient control is also not mentioned.

Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-David discloses nerve stimulation for treating disorders. A control unit drives an electrode device to stimulate the vagus nerve, so as to modify heart rate variability, or to reduce heart rate, by suppressing the adrenergic (sympathetic) system. Patient control is not mentioned. The vagal stimulation reduces the release of catecholamines in the heart, thus lowering adrenergic tone at its source. For some applications, the control unit synchronizes the stimulation with the cardiac cycle, while for other applications, the stimulation can be applied, for example, in a series of pulses. To reduce heart rate, stimulation is applied using a target heart rate lower than the subject's normal average heart rate.

Accordingly, a need remains for an approach to therapeutically treating chronic cardiac dysfunction, including CHF, through a form of VNS to restore autonomic balance and enable the patient to exercise control over therapy delivery and suspension.

SUMMARY

Excessive sustained activation of the sympathetic nervous system has a deleterious effect on long term cardiac performance and on the quality of life and survival of patients suffering from chronic cardiac dysfunction. Bi-directional afferent and efferent neural stimulation through the vagus nerve can beneficially restore autonomic balance and improve long term patient outcome. VNS delivery can be provided through an implantable vagal neurostimulator and electrode lead, which includes a remotely-actuatable switch that enables external triggering of different modes of therapeutic operation.

One embodiment provides a multi-modal vagus nerve neurostimulator for treating chronic cardiac dysfunction. An implantable neurostimulator includes a pulse generator configured to deliver electrical therapeutic stimulation tuned to restore autonomic balance through continuously-cycling, intermittent and periodic electrical pulses delivered in both afferent and efferent directions of a cervical vagus nerve through a pair of helical electrodes via an electrically coupled nerve stimulation therapy lead. An external electromagnetic controller is configured to transmit a plurality of magnetic signals uniquely associated with operating modes, the neurostimulator switching to the corresponding operating mode in response to the magnetic signal.

A further embodiment provides a vagus nerve neurostimulator system with multiple patient-selectable modes for treating chronic cardiac dysfunction. An implantable neurostimulator includes a pulse generator coupled to a therapy lead terminated by a pair of helical electrodes positioned over a cervical vagus nerve. The pulse generator is configured to deliver through the helical electrodes continuously-cycling, intermittent and periodic electrical stimulation that is parametrically defined to bi-directionally propagate through nerve fibers in the cervical vagus nerve. The implantable neurostimulator also includes a magnetic switch configured to switch the pulse generator between a plurality of operating modes that are each separately selectable in response to a unique and remotely-applied magnetic signal. An external controller includes patient-actuatable controls configured to enable selection of one of the operating modes of the pulse generator. The external controller also includes an electromagnetic transmitter configured to output the magnetic signal uniquely associated with the operating mode as selected with the controls.

A still further embodiment provides a vagus nerve neurostimulator system for treating chronic cardiac dysfunction with multiple remotely patient-selectable modes. A cervical vagus nerve stimulation therapy lead includes a pair of helical electrodes configured to conform to an outer diameter of a cervical vagus nerve sheath of a patient and a set of connector pins electrically connected to the helical electrodes by an insulated electrical lead body. A neurostimulator is powered by a primary battery and enclosed in a hermetically sealed housing. The neurostimulator further includes an electrical receptacle included on an outer surface of the housing into which the connector pins are securely and electrically coupled. The neurostimulator also includes a pulse generator configured to therapeutically stimulate the cervical vagus nerve through the helical electrodes by delivering continuously-cycling, intermittent and periodic electrical stimulation that is tuned to both efferently activate the heart's intrinsic nervous system and afferently activate the patient's central reflexes by triggering bi-directional action potentials. Finally, the neurostimulator includes a magnetic switch configured to switch the pulse generator between a plurality of operating modes that are each separately selectable in response to a unique and remotely-applied magnetic signal. The operating modes include one or more of a high therapeutic dosage, therapy titration, therapy suspension, and sleep modes. An external patient controller includes patient-actuatable controls configured to accept an input from a patient indication a selection of one of the pulse generator's operating modes. The external patient controller also includes an electromagnetic transmitter configured to output the magnetic signal uniquely associated with the selected operating mode. Finally, the external patient controller includes a patient feedback device configured to output to the patient an indication of acceptance of the selection by the neurostimulator.

By restoring autonomic balance, therapeutic VNS operates acutely to decrease heart rate, increase heart rate variability and coronary flow, reduce cardiac workload through vasodilation, and improve left ventricular relaxation. Over the long term, VNS provides the chronic benefits of decreased negative cytokine production, increased baroreflex sensitivity, increased respiratory gas exchange efficiency, favorable gene expression, renin-angiotensin-aldosterone system down-regulation, and anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects. Additionally, patient-accessible control to an expanded set of operational modes, including temporary or indefinite therapy suspension, higher dosage, sleep mode, and initiation of automated titration, and allow on-the-fly adjustment of VNS tailored to the patient's needs.

Still other embodiments of the present invention will become readily apparent to those skilled in the art from the following detailed description, wherein are described embodiments by way of illustrating the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments and its several details are capable of modifications in various obvious respects, all without departing from the spirit and the scope of the present invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example, placement of an implantable vagus stimulation device in a male patient, in accordance with one embodiment.

FIG. 2 is a diagram showing the implantable neurostimulator and simulation therapy lead of FIG. 1 with the therapy lead unplugged.

FIG. 3 is a diagram showing an external programmer for use with the implantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing the helical electrodes provided as on the stimulation therapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship between the targeted therapeutic efficacy and the extent of potential side effects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cycle range based on the intersection depicted in FIG. 5.

FIG. 7 is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS as provided by implantable neurostimulator of FIG. 1.

FIG. 8 is a diagram showing a simple patient magnet for use with the implantable neurostimulator of FIG. 1.

FIG. 9 is a diagram showing a patient electromagnetic controller for use with the implantable neurostimulator of FIG. 1.

DETAILED DESCRIPTION

Functional behavior of heart tissue is influenced by the autonomic nervous system, which is known to play a key pathogenic role in the cause of and the biological response to cardiovascular disease. The sympathetic nervous system affects cardiovascular physiology in an “all-or-nothing” neurological response, whereas the parasympathetic nervous system selectively modulates specific regions of the heart at various levels of activation. Through these two nervous systems, the autonomic nervous system directly controls the heart by affecting conduction velocity, refractoriness, impulse formation, and other electrophysiological properties of the cardiac tissue, and indirectly by influencing the heart's hemodynamics, coronary blood flow, and metabolism, as well as exercising control over other critical body functions that rely on the heart. Complex changes in autonomic control of the cardiovascular systems of patients suffering from a cardiovascular disease, though, push the autonomic nervous system out of balance and favor increased sympathetic and decreased parasympathetic central outflow.

The sympathetic and parasympathetic nervous systems dynamically interact through signals partially modulated by cAMP and cGMP secondary messengers to presynaptically influence the activation of each other's nerve traffic. Through these messengers, changes to one nervous system can indirectly affect nerve activation in the other. For instance, during autonomic imbalance, sympathetic neural activity increases while cardiac vagal activation is withdrawn. In view of their collaborative influence over cardiavascular function, the restoration of autonomic balance between these nervous systems is a crucial part of effectively managing chronic cardiac dysfunction.

Peripheral neurostimulation therapies that target the imbalance of the autonomic nervous system found in individuals with severe CHF have been shown to improve outcomes. Conventional therapeutic alteration of cardiac vagal efferent activation through electrical stimulation of parasympathetic vagal nerve fibers can produce beneficial bradycardia and modification in atrial and ventricular contractile function. However, the targeting of only the efferent nerves of the parasympathetic nervous system is clinically insufficient to restore autonomic balance. Any therapeutic effect on parasympathetic activation occurs as a result of incidental recruitment of afferent parasympathetic nerve fibers and not as an intended and desired outcome. In contrast, propagating bi-directional action potentials through bi-directional autonomic regulation therapy activates both parasympathetic afferent and efferent nerve fibers in the vagus nerve simultaneously. The therapy works to directly restore autonomic balance by engaging both medullary and cardiac reflex control components of the autonomic nervous system. Upon stimulation of the cervical vagal nerve, action potentials propagate away from the stimulation site in two directions, efferently toward the heart and afferently toward the brain. Efferent action potentials influence the intrinsic cardiac nervous system and the heart, while afferent action potentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treat drug-refractory epilepsy and depression, can be adapted for use in managing chronic cardiac dysfunction through therapeutic bi-directional vagal stimulation in conjunction with an external patient-actuatable controller that enables external triggering of different modes of therapeutic operation. FIG. 1 is a front anatomical diagram showing, by way of example, placement of an implantable vagus stimulation device 11 in a male patient 10, in accordance with one embodiment. The VNS provided through the stimulation device 11 operates under several mechanisms of action. These mechanisms include increasing parasympathetic outflow and inhibiting sympathetic effects by blocking norepinephrine release. More importantly, VNS triggers the release of acetylcholine (ACh) into the synaptic cleft, which has beneficial anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects.

The implantable vagus stimulation device 11 includes three implanted components, an implantable neurostimulator 12, a therapy lead 13, and helical electrodes 14. The implantable vagus stimulation device 11 can be remotely accessed following implant through three different external components, an external programmer (as further described below with reference to FIG. 3) by which the neurostimulator 12 can be remotely checked and programmed by healthcare professionals, an external magnet (as further described below with reference to FIG. 8) for basic patient control, and an electromagnetic controller (as further described below with reference to FIG. 9) that enables the patient 10 to exercise increased control over therapy delivery and suspension. Together, the implantable vagus stimulation device 11 and one or more of the external components form a VNS therapeutic delivery system.

The neurostimulator 12 is implanted in the patient's right or left pectoral region generally on the same side (ipsilateral) of the patient's body as the vagus nerve 15, 16 to be stimulated. A subcutaneous pocket is formed in the subclavicular region into which the neurostimulator 12 is placed. The helical electrodes 14 are generally implanted on the vagus nerve 15, 16 about halfway between the clavicle 19 a-b and the mastoid process. The therapy lead 13 and helical electrodes 14 are implanted by first exposing the carotid sheath and chosen vagus nerve 15, 16 through a latero-cervical incision on the ipsilateral side of the patient's neck 18. The helical electrodes 14 are then placed onto the exposed nerve sheath and tethered. A subcutaneous tunnel is formed between the respective implantation sites of the neurostimulator 12 and helical electrodes 14, through which the therapy lead 13 is guided to the neurostimulator 12 and securely connected.

Anatomically, the vagus nerve includes a pair of nerve fiber bundles 15, 16 that both proceed laterally through the neck, thorax, and abdomen, and distally innervate the heart 17 and other major organs and body tissue. The stimulation device 11 bi-directionally stimulates the vagus nerve 15, 16 through application of continuously-cycling, intermittent and periodic electrical stimuli, which are parametrically defined through stored stimulation parameters and timing cycles. Both sympathetic and parasympathetic nerve fibers are stimulated through the helical electrodes 14 of the stimulation device 11. Stimulation of the cervical vagus nerve results in propagation of action potentials in both afferent and efferent directions from the site of stimulation. Afferent action potentials propagate toward the parasympathetic nervous system's origin in the medulla in the nucleus ambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, as well as towards the sympathetic nervous system's origin in the intermediolateral cell column of the spinal cord.

Efferent action potentials propagate toward the heart to activate the components of the heart's intrinsic nervous system (intrinsic cardiac nervous system). Epicardially, the cardiac nervous system is conceived as two major outflow branches exerting reciprocal control over cardiac indices under sole influence of central neuronal command. The outflow branches respectively regulate adrenergic (sympathetic) and cholinergic (parasympathetic) efferent preganglionic neuronal activity. Innervation of the heart 17 is regionalized and exhibits a high degree of asymmetry. Within the heart 17, the greatest concentration of vagal nerves is found first in the sinus node and then in the atrioventricular node. Cardiac efferents of the left vagus nerve 15 predominantly, but not exclusively, regulate cardiac contractility through their influence on conduction in the atrioventricular (AV) node. Cardiac efferents of the right vagus nerve 16 predominantly, but not exclusively, affect sinus node automaticity and regulate heart rate. Thus, right-sided cervical vagal stimulation tends to produce sinus bradycardia, whereas left-sided cervical vagal stimulation tends to produce AV nodal blockage.

Either the left or right vagus nerve 15, 16 can be stimulated by the stimulation device 11, although stimulation of the left vagus nerve 15 is preferred because stimulation of the left vagus nerve 15 is less likely to be arrhythmogenic. The left vagus nerve 15 has fewer projections to the sinoatrial node and is therefore less likely to severely reduce sinus heart rate. Left VNS can modestly increase AV nodal conduction time and refractory period, although, at therapeutic levels of VNS for treatment of chronic heart dysfunction, AV nodal conduction time and refractory period are minimally affected.

VNS elicits bi-directional activation of both afferent and efferent nerve fibers. The vagus nerve 15, 16 is composed of nerve fibers that are 80% afferent and only 20% efferent, indicating that the afferent component of action potential propagation to activate the central nervous system is a critical part of the beneficial therapeutic effects. Moreover, the balance between achieving therapeutic benefits (afferent) and side-effects (efferent) is largely determined by the threshold differences between activation of the different vagus nerve fibers. For instance, large diameter nerve fibers reach activation threshold at lower stimulation intensities than small diameter nerve fibers. Additionally, the respective thresholds of B-fibers and C-fibers are approximately 2-3 and 10-100 times higher than the threshold of A-fibers. Consequently, recruitment of vagal nerve fibers in response to VNS by the stimulation device 11 is largely governed by, and occurs in order of decrease nerve fiber diameter, such that A-fibers are activated first, then B-fibers, and finally C-fibers.

The VNS therapy is autonomously delivered to the patient's vagus nerve 15, 16 through three implanted components, a neurostimulator 12, therapy lead 13, and helical electrodes 14. FIG. 2 is a diagram showing the implantable neurostimulator 12 and simulation therapy lead 13 of FIG. 1 with the therapy lead unplugged 20. In one embodiment, the neurostimulator 12 can be adapted from a VNS Therapy AspireHC Model 105 generator or a VNS Therapy AspireSR Model 106, both manufactured and sold by Cyberonics, Inc., Houston, Tex., although other manufactures and types of single-pin receptacle implantable VNS neurostimulators could also be used. The stimulation therapy lead 13 and helical electrodes 14 are generally fabricated as a combined assembly and can be adapted from a Model 302 lead, PerenniaDURA Model 303 lead, or PerenniaFLEX Model 304 lead, all of which are also manufactured and sold by Cyberonics, Inc., in two sizes based on helical electrode inner diameter, although other manufactures and types of single-pin receptacle-compatible therapy leads and electrodes could also be used.

The neurostimulator 12 provides continuously-cycling, intermittent and periodic ON-OFF cycles of vagal stimulation that when applied to the vagus nerve through the electrodes 14, produce action potentials in the underlying nerves that propagate bi-directionally; afferently propagating action potentials activate the medial medullary sites responsible for central reflex control and efferently propagating action potentials activate both the heart's intrinsic nervous system and the heart directly. Cardiac motor neurons, when activated, influence heart rate, AV nodal conduction, and atrial and ventricular inotropy, thereby providing therapeutic effects to chronically-dysfunctional cardiac tissues. In addition, the continuously alternating cycles of intermittent stimulation can be tuned to activate and promote immediate and persistent phasic parasympathetic response in the vagus nerve 15, 16 being stimulated by bi-directionally modulating vagal tone.

The neurostimulator 12 includes an electrical pulse generator that delivers continuously-cycling, intermittent and periodic electrical therapeutic stimulation, which is tuned to restore autonomic balance, through action potentials that propagate both afferently and efferently within the vagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermetically sealed housing 21 constructed of a biocompatible, implantation-safe material, such as titanium. The housing 21 contains electronic circuitry 22 powered by a primary battery 22, such as a lithium carbon monoflouride battery. The electronic circuitry 22 is implemented using complementary metal oxide semiconductor integrated circuits that include a microprocessor that executes a control program according to stored stimulation parameters and timing cycles; a voltage regulator that regulates system power; logic and control circuitry, including a recordable memory 29 within which the stimulation parameters are stored, that controls overall pulse generator function, receives and implements programming commands from the external programmer, or other external source, and collects and stores telemetry information; a transceiver that remotely communicates with the external programmer using radio frequency signals; an antenna, which receives programming instructions and transmits the telemetry information to the external programmer; and a reed switch 30 that provides remote access to the operation of the neurostimulator 12 using a programmer (as further described below with reference to FIG. 3), a simple patient magnet (as further described below with reference to FIG. 8), or an electromagnetic controller (as further described below with reference to FIG. 9). The recordable memory 29 can include both volatile (dynamic) and persistent (static) forms of memory, such as firmware within which the stimulation parameters and timing cycles can be stored. Other electronic circuitry and components, such as an integrated heart rate sensor, are possible.

The neurostimulator 12 delivers VNS under control of the electronic circuitry 22, particularly the logic and control circuitry, which control stimulus delivery per a schedule specified in the stored stimulation parameters or on-demand in response to magnet mode, a programming wand instruction, or other external source. The stored stimulation parameters are programmable (as further described below with reference to FIG. 7). In addition, sets of pre-selected stimulation parameters can be provided to physicians through the external programmer and fine-tuned to a patient's physiological requirements prior to being programmed into the neurostimulator 12, such as described in commonly-assigned U.S. patent application, entitled “Computer-Implemented System and Method for Selecting Therapy Profiles of Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7, 2011, pending, the disclosure of which is incorporated by reference. The stimulation parameters also include the levels of stimulation for the bi-directional action potentials.

Externally, the neurostimulator 12 includes a header 24 to securely receive and connect to the therapy lead 13. In one embodiment, the header 24 encloses a receptacle 25 into which a single pin for the therapy lead 13 can be received, although two or more receptacles could also be provided, along with the requisite additional electronic circuitry 22. The header 24 internally includes a lead connector block (not shown) and a set of set screws 26.

The therapy lead 13 delivers an electrical signal from the neurostimulator 12 to the vagus nerve 15, 16 via the helical electrodes 14. On a proximal end, the therapy lead 13 has a lead connector 27 that transitions an insulated electrical lead body to a metal connector pin 28. During implantation, the connector pin 28 is guided through the receptacle 25 into the header 24 and securely fastened in place using the set screws 26 to electrically couple the therapy lead 13 to the neurostimulator 12. On a distal end, the therapy lead 13 terminates with the helical electrode 14, which bifurcates into a pair of anodic and cathodic electrodes 62 (as further described below with reference to FIG. 4). In one embodiment, the lead connector 27 is manufactured using silicone and the connector pin 28 is made of stainless steel, although other suitable materials could be used, as well. The insulated lead body 13 utilizes a silicone-insulated alloy conductor material.

The neurostimulator 12 is preferably interrogated prior to implantation and throughout the therapeutic period for checking proper operation, downloading recorded data, diagnosing problems, and programming operational parameters. FIG. 3 is a diagram showing an external programmer 40 for use with the implantable neurostimulator 12 of FIG. 1. The external programmer 40 includes a healthcare provider-operable programming computer 41 and a programming wand 42. Generally, use of the external programmer 40 is restricted to healthcare providers, while more limited manual control is provided to the patient through “magnet mode.”

In one embodiment, the programming computer 41 executes application software specially designed to interrogate the neurostimulator 12. The programming computer 41 interfaces to the programming wand 42 through a standardized wired data connection, including a serial data interface, for instance, an EIA RS-232 or USB serial port. Alternatively, the programming computer 41 and the programming wand 42 could interface wirelessly. The programming wand 42 can be adapted from a Model 201 Programming Wand, manufactured and sold by Cyberonics, Inc. Similarly, the application software can be adapted from the Model 250 Programming Software suite, licensed by Cyberonics, Inc. Other configurations and combinations of computer 41, programming wand 42, and application software 45 are possible.

The programming computer 41 can be implemented using a general purpose programmable computer and can be a personal computer, laptop computer, netbook computer, handheld computer, or other form of computational device. In one embodiment, the programming computer is a personal digital assistant handheld computer operating under the Pocket-PC or Windows Mobile operating systems, licensed by Microsoft Corporation, Redmond, Wash., such as the Dell Axim X5 and X50 personal data assistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personal data assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. The programming computer 41 functions through those components conventionally found in such devices, including, for instance, a central processing unit, volatile and persistent memory, touch-sensitive display, control buttons, peripheral input and output ports, and network interface. The computer 41 operates under the control of the application software 45, which is executed as program code as a series of process or method modules or steps by the programmed computer hardware. Other assemblages or configurations of computer hardware, firmware, and software are possible.

Operationally, the programming computer 41, when connected to a neurostimulator 12 through wireless telemetry using the programming wand 42, can be used by a healthcare provider to remotely interrogate the neurostimulator 12 and modify stored stimulation parameters. The programming wand 42 provides data conversion between the digital data accepted by and output from the programming computer and the radio frequency signal format that is required for communication with the neurostimulator 12.

The healthcare provider operates the programming computer 41 through a user interface that includes a set of input controls 43 and a visual display 44, which could be touch-sensitive, upon which to monitor progress, view downloaded telemetry and recorded physiology, and review and modify programmable stimulation parameters. The telemetry can include reports on device history that provide patient identifier, implant date, model number, serial number, magnet activations, total ON time, total operating time, manufacturing date, and device settings and stimulation statistics and on device diagnostics that include patient identifier, model identifier, serial number, firmware build number, implant date, communication status, output current status, measured current delivered, lead impedance, and battery status. Other kinds of telemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46 and the bottom surface 47 of the programming wand 42 is placed on the patient's chest over the location of the implanted neurostimulator 12. A set of indicator lights 49 can assist with proper positioning of the wand and a set of input controls 48 enable the programming wand 42 to be operated directly, rather than requiring the healthcare provider to awkwardly coordinate physical wand manipulation with control inputs via the programming computer 41. The sending of programming instructions and receipt of telemetry information occur wirelessly through radio frequency signal interfacing. Other programming computer and programming wand operations are possible.

Preferably, the helical electrodes 14 are placed over the cervical vagus nerve 15, 16 at the location below where the superior and inferior cardiac branches separate from the cervical vagus nerve. FIG. 4 is a diagram showing the helical electrodes 14 provided as on the stimulation therapy lead 13 of FIG. 2 in place on a vagus nerve 15, 16 in situ 50. Empirically, the thresholds and recruitment of vagal nerve fibers have been demonstrated to be unaffected by either electrode configuration or stimulation waveform. In one embodiment, helical electrodes 14 are employed for delivering the electrical stimulation, although other configurations, as well as stimulation waveforms, are possible. In addition, although described with reference to a specific manner and orientation of implantation, the specific surgical approach and implantation site selection particulars may vary, depending upon physician discretion and patient physical structure.

The helical electrodes 14 are positioned over the patient's vagus nerve 61 oriented with the end of the helical electrodes 14 facing the patient's head. At the distal end, the insulated electrical lead body 13 is bifurcated into a pair of lead bodies 57, 58 that are connected to a pair of electrodes proper 51, 52. The polarity of the electrodes 51, 52 could be configured into a monopolar cathode, a proximal anode and a distal cathode, or a proximal cathode and a distal anode. In addition, an anchor tether 53 is fastened over the lead bodies 57, 58 that maintains the helical electrodes' position on the vagus nerve 61 following implant. In one embodiment, the conductors of the electrodes 51, 52 are manufactured using a platinum and iridium alloy, while the helical materials of the electrodes 51, 52 and the anchor tether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 are coiled around the vagus nerve 61 proximal to the patient's head, each with the assistance of a pair of sutures 54, 55, 56, made of polyester or other suitable material, which help the surgeon to spread apart the respective helices. The lead bodies 57, 58 of the electrodes 51, 52 are oriented distal to the patient's head and aligned parallel to each other and to the vagus nerve 61. A strain relief bend 60 can be formed on the distal end with the insulated electrical lead body 13 aligned parallel to the helical electrodes 14 and attached to the adjacent fascia by a plurality of tie-downs 59 a-b.

In one embodiment, the stimulation protocol calls for a six-week titration period. During the first three-weeks, the surgical incisions are allowed to heal and no VNS therapy occurs. During the second three-weeks, the neurostimulator 12 is first turned on and operationally tested. The impulse rate and intensity of the VNS is then gradually increased every three or four days until full therapeutic levels of stimulation are achieved, or maximal patient tolerance is reached, whichever comes first. Patient tolerance can be gauged by physical discomfort, as well as based on presence of known VNS side-effects, such as ataxia, coughing, hoarseness, or dyspnea.

Therapeutically, the VNS is delivered through continuously-cycling, intermittent and periodic cycles of electrical pulses and rest (inhibition), which are system output behaviors that are pre-specified within the neurostimulator 12 through the stored stimulation parameters and timing cycles implemented in firmware and executed by the microprocessor. The neurostimulator 12 can operate either with or without an integrated heart rate sensor, such as respectively described in commonly-assigned U.S. patent application, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction with Leadless Heart Rate Monitoring,” Ser. No. 13/314,126, filed on Dec. 7, 2011, pending, and U.S. patent application, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011, pending, the disclosures of which are incorporated by reference. Additionally, where an integrated leadless heart rate monitor is available, the neurostimulator 12 can provide autonomic cardiovascular drive evaluation and self-controlled titration, such as respectively described in commonly-assigned U.S. patent application, entitled “Implantable Device for Evaluating Autonomic Cardiovascular Drive in a Patient Suffering from Chronic Cardiac Dysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, pending, and U.S. patent application, entitled “Implantable Device for Providing Electrical Stimulation of Cervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction with Bounded Titration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, pending, the disclosures of which are incorporated by reference.

A “duty cycle” is the percentage of time that the neurostimulator 12 is stimulating, that is, the percentage of ON times. The VNS can be delivered with a periodic duty cycle in the range of 2% to 89% with a preferred range of around 4% to 36%. The selection of duty cycle is a tradeoff between competing medical considerations. FIG. 5 is a graph 70 showing, by way of example, the relationship between the targeted therapeutic efficacy 73 and the extent of potential side effects 74 resulting from use of the implantable neurostimulator 12 of FIG. 1. The x-axis represents the duty cycle 71. The duty cycle is determined by dividing the stimulation time by the sum of the ON and OFF times of the neurostimulator 12. However, the stimulation time may also need to include ramp-up time and ramp-down time, where the stimulation frequency exceeds a minimum threshold (as further described below with reference to FIG. 7). The y-axis represents physiological response 72 to VNS therapy. The physiological response 72 can be expressed quantitatively for a given duty cycle 71 as a function of the targeted therapeutic efficacy 73 and the extent of potential side effects 74, as described infra. The maximum level of physiological response 72 (“max”) signifies the highest point of targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential side effects 74 can be expressed as functions of duty cycle 71 and physiological response 72. The targeted therapeutic efficacy 73 represents the intended effectiveness of VNS in provoking a beneficial physiological response for a given duty cycle and can be quantified by assigning values to the various acute and chronic factors that contribute to the physiological response 72 of the patient 10 due to the delivery of therapeutic VNS. Acute factors that contribute to the targeted therapeutic efficacy 73 include increase in heart rate variability and coronary flow, reduction in cardiac workload through vasodilation, and improvement in left ventricular relaxation. Chronic factors that contribute to the targeted therapeutic efficacy 73 include decreased parasympathetic activation and increased sympathetic activation, as well as decreased negative cytokine production, increased baroreflex sensitivity, increased respiratory gas exchange efficiency, favorable gene expression, renin-angiotensin-aldosterone system down-regulation, anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatory effects. These contributing factors can be combined in any manner to express the relative level of targeted therapeutic efficacy 73, including weighting particular effects more heavily than others or applying statistical or numeric functions based directly on or derived from observed physiological changes. Empirically, targeted therapeutic efficacy 73 steeply increases beginning at around a 5% duty cycle, and levels off in a plateau near the maximum level of physiological response at around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73 begins decreasing at around a 50% duty cycle and continues in a plateau near a 25% physiological response through the maximum 100% duty cycle.

The extent of potential side effects 74 represents the occurrence of a possible physiological effect, either adverse or therapeutic, that is secondary to the benefit intended, which presents in the patient 10 in response to VNS and can be quantified by assigning values to the physiological effects presented due to the delivery of therapeutic VNS. The degree to which a patient 10 may be prone to exhibit side effects depends in large part upon the patient's condition, including degree of cardiac dysfunction, both acute and chronic, any comobidities, prior heart problems, family history, general health, and similar considerations. As well, the type and severity of a side effect is patient-dependent. For VNS in general, the more common surgical- and stimulation-related adverse side effects include infection, asystole, bradycardia, syncope, abnormal thinking, aspiration pneumonia, device site reaction, acute renal failure, nerve paralysis, hypesthesia, facial paresis, vocal cord paralysis, facial paralysis, hemidiaphragm paralysis, recurrent laryngeal injury, urinary retention, and low grade fever. The more common non-adverse side effects include hoarseness (voice alteration), increased coughing, pharyngitis, paresthesia, dyspnea, dyspepsia, nausea, and laryngismus. Less common side effects, including adverse events, include ataxia, hypesthesia, increase coughing, insomnia, muscle movement or twitching associated with stimulation, nausea, pain, paresthesia, pharyngitis, vomiting, aspiration, blood clotting, choking sensation, nerve damage, vasculature damage, device migration or extrusion, dizziness, dysphagia, duodenal or gastric ulcer, ear pain, face flushing, facial paralysis or paresis, implant rejection, fibrous tissue formation, fluid pocket formation, hiccupping, incision site pain, irritability, laryngeal irritation, hemidiaphragm paralysis, vocal cord paralysis, muscle pain, neck pain, painful or irregular stimulation, seroma, skin or tissue reaction, stomach discomfort, tinnitus, tooth pain, unusual scarring at incision site, vagus nerve paralysis, weight change, worsening of asthma or bronchitis. These quantified physiological effects can be combined in any manner to express the relative level of extent of potential side effects 74, including weighting particular effects more heavily than others or applying statistical or numeric functions based directly on or derived from observed physiological changes. Empirically, the extent of potential side effects 74 is initially low until around a 25% duty cycle, at which point the potential begins to steeply increase. The extent of potential side effects 74 levels off in a plateau near the maximum level of physiological response at around a 50% duty cycle through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and the extent of potential side effects 74 represents the optimal duty cycle range for VNS.

FIG. 6 is a graph 80 showing, by way of example, the optimal duty cycle range 83 based on the intersection 75 depicted in FIG. 5. The x-axis represents the duty cycle 81 as a percentage of stimulation time over inhibition time. The y-axis represents the desirability 82 of operating the neurostimulator 12 at a given duty cycle 81. The optimal duty range 83 is a function 84 of the intersection 74 of the targeted therapeutic efficacy 73 and the extent of potential side effects 74. The desirability 82 can be expressed quantitatively for a given duty cycle 81 as a function of the values of the targeted therapeutic efficacy 73 and the extent of potential side effects 74 at their point of intersection in the graph 70 of FIG. 5. The maximum level of desirability 82 (“max”) signifies a tradeoff that occurs at the point of highest targeted therapeutic efficacy 73 in light of lowest potential side effects 74 and that point will typically be found within the range of a 5% to 30% duty cycle 81. Other expressions of duty cycles and related factors are possible.

The neurostimulator 12 delivers VNS according to stored stimulation parameters, which are programmed using an external programmer 40 (shown in FIG. 3). Each stimulation parameter can be independently programmed to define the characteristics of the cycles of therapeutic stimulation and inhibition to ensure optimal stimulation for a patient 10. The programmable stimulation parameters affecting stimulation include output current, signal frequency, pulse width, signal ON time, signal OFF time, magnet activation (for VNS specifically triggered by “magnet mode”), and reset parameters. Other programmable parameters are possible.

VNS is delivered in alternating cycles of stimuli application and stimuli inhibition that are tuned to both efferently activate the heart's intrinsic nervous system and heart tissue and afferently activate the patient's central reflexes. FIG. 7 is a timing diagram showing, by way of example, a stimulation cycle and an inhibition cycle of VNS 90 as provided by implantable neurostimulator 12 of FIG. 1. The stimulation parameters enable the electrical stimulation pulse output by the neurostimulator 12 to be varied by both amplitude (output current 96) and duration (pulse width 94). The number of output pulses delivered per second determines the signal frequency 93. In one embodiment, a pulse width in the range of 100 to 250 μsec delivers between 0.02 and 50 mA of output current at a signal frequency of about 20 Hz, although other therapeutic values could be used as appropriate.

In the simplest case, the stimulation time is the time period during which the neurostimulator 12 is ON and delivering pulses of stimulation. The OFF time 95 is always the time period occurring in-between stimulation times 91 during which the neurostimulator 12 is OFF and inhibited from delivering stimulation. In one embodiment, the neurostimulator 12 implements a ramp-up time 97 and a ramp-down time 98 that respectively precede and follow the ON time 92 during which the neurostimulator 12 is ON and delivering pulses of stimulation at the full output current 96. The ramp-up time 97 and ramp-down time 98 are used when the stimulation frequency is at least 10 Hz, although other minimum thresholds could be used, and both times last two seconds, although other time periods could also be used. The ramp-up time 97 and ramp-down time 98 allow the strength of the output current 96 of each output pulse to be gradually increased and decreased, thereby avoiding unnecessary trauma to the vagus nerve due to sudden delivery or inhibition of stimulation at full strength.

For safety reasons, most neurostimulators include a “magnet mode” that enables a patient to exercise limited manual control over the device. FIG. 8 is a diagram showing a simple patient magnet 100 for use with the implantable neurostimulator 12 of FIG. 1. The patient magnet 100 can be used by a patient or healthcare provider to remotely trigger the reed switch 30 (shown in FIG. 2) that is contained inside the housing 21 of the neurostimulator 12. In one embodiment, the patient magnet 100 can be adapted from a Model 250 magnet, manufactured and sold by Cyberonics, Inc., although other manufactures and types of patient magnets could also be used.

Physically, the patient magnet 100 is a portable magnet that is capable of sending a magnetic signal through the patient's upper chest region with sufficient strength to trip the reed switch 30 in an implanted neurostimulator 12 when placed in close proximity to the implantation site, such as described in commonly-assigned U.S. patent application, entitled “Implantable Device For Facilitating Control Of Electrical Stimulation Of Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,” Ser. No. 13/314,130, filed on Dec. 7, 2011, pending, the disclosure of which is incorporated by reference. The surface 101 of the patient magnet 100 must be applied to or swiped over the implantation site on the patient's chest. The reed switch 30 then switches the neurostimulator 12 into a different mode of operation or inhibition.

Ensuring proper “magnet mode” activation is crucial to patient safety. Incorrect use of the patient magnet 100 carries significant risk and could lead to accidental shutdown of the neurostimulator 12 or unintended alteration of therapy. As a result, the triggering of the reed switch 30 using a handheld patient magnet 100 is limited to as few as two modes of operation, which can be accessing through simple and easy-to-perform magnet swipe patterns. Notwithstanding, the flexibility of VNS therapy can be improved by allowing the neurostimulator 12 to operate under a richer set of operating modes. A unique pattern of magnetic signals could be assigned to initiate each of the different operating modes. However, increasingly complex patterns of magnetic signals quickly exceed the abilities of the average patient by being difficult to remember and perform, yet are necessary to sufficiently differentiate between the operating mode desired.

To enable a wider range of neurostimulator operating modes, the simple patient magnet 100 can be replaced by an electromagnetic signal transmitter that electronically executes the patterns of magnetic signals for the patient 10. FIG. 9 is a diagram showing a patient electromagnetic controller 110 for use with the implantable neurostimulator 12 of FIG. 1. The patient electromagnetic controller 110 includes a housing 111 upon which a set of one or more patient-actuatable input controls 112 a-d are provided.

The housing 111 can be formed into a convenient hand-holdable shape to facilitate easy placement over the chest. Internally, a switchable electromagnet outputs a different pattern of magnetic signals from the patient-facing surface 115 of the electromagnetic controller 110 in response to operation of the input controls 112 a-d. A single input control, such as a key or push button, can be provided for each different operating mode, or a multi-modal input control, such as a toggle or rocker switch, joy stick, or selector knob, could be provided, which the patient 10 would use to choose the operating mode desired. In addition, patient feedback can be respectively provided through an output device to indicate acceptance of the chosen operating mode by the neurostimulator 12 and other status indicators. The output device can include a built-in speaker 113 and indicator light 114, which respectively output visual and audible indications to the patient 10. Other types of output devices are possible, including tactile feedback mechanisms that, for instance, vibrate or shake the housing 111. The indicator light 114 could display multiple colors to indicate, for instance, power on, proper placement over the neurostimulator 12, and successful triggering of the reed switch 30. Similarly, the speaker 113 could generate a single beep to confirm proper placement and a series of beeps to indicate successful triggering. In a further embodiment, a series of verbal instructions could be played through the speaker 113. As well, the indicator light 114 could be an alphanumeric or graphical display, such as an LCD or LED display, that displays instructions, status, and progress indications. Finally, in a still further embodiment, the alphanumeric or graphical display could include a touch-sensitive interface that either replaces or supplements the patient-actuatable controls. Still other types and combinations of input controls and output feedback components are possible.

The selection and operation of an input control 112 a-d causes the electromagnetic controller 110 to generate a magnetic signal pattern that causes the neurostimulator 12 to switch to a different operating mode. A different magnetic signal is assigned to each operating mode of the neurostimulator 12. The internal electromagnet circuitry ensures that the correct magnetic signal pattern is output, thereby facilitating ease-of-use by freeing the patient 10 of the need to manually swipe and apply a magnet over the neurostimulator 12. Moreover, the patient 10 need not master a long list of magnetic signal patterns, which can become increasingly complex with the number of operating modes.

By way of example, the input controls 112 a-d can correspond to sleep, suspend, titration, and higher duty cycle (“High Dose”) modes of operation. Using the “Sleep” input control 112 a, the patient 10 can temporarily inhibit or reduce stimulation for a fixed time period, such as at night from six to eight hours to sleep, during which heart rate naturally slows down. Therapy can be programmed to resume automatically after the fixed time period.

Using the “Suspend” input control 112 b, the patient 10 can stop stimulation indefinitely. For instance, a device or lead failure can cause improper stimulation that results in muscle stimulation and pain. The patient 10 can stop stimulation and seek medical assistance. Similarly, if the patient 10 feels the onset of bradycardia or an asystolic heart condition, the neurostimulator 12 can be instructed to completely suspend the triggering of the bi-directional action potentials, either all at once or by gradually reducing VNS therapy levels over a fixed time period, amplitude-related time (fixed rate of decline) period or programmable time period. Alternatively, the neurostimulator 12 can be instructed to down-titrate therapy in response to the “Suspend” input control 112 b by gradually reducing the stimulation parameters until the bradycardia is no longer present. Therapy can then be programmed to gradually up-titrate therapy by adjusting the stimulation parameters upwards after first inhibiting stimulation for a fixed time period.

Using the “Titration” input control 112 c, the patient 10 can trigger the neurostimulator 12 to initiate a titration protocol on a periodic (daily, weekly, monthly, and so on) basis or when triggered, such as in response to discomfort. For instance, the therapy can be programmed to gradually up-titrate to a new higher threshold by adjusting the stimulation parameters to a higher intensity level. Similarly, the therapy can be programmed to gradually down-titrate to a new lower threshold by adjusting the stimulation parameters to a lower intensity level. Both the up-titration and the down-titration can occur stepwise, where the changes in the stimulation parameters occur in small increments spread out over time, rather than all at once. In a further embodiment, the neurostimulator 12 could be programmed to automatically titrate on a schedule without patient intervention. The patient 10 would use the “Titration” input control 112 c to initiate up-titration in response to a side-effect-free period of time, or down-titration in response to a side effect. VNS therapy can be titrated by adjusting the stored stimulation parameters, including pulse amplitude, pulse current, pulse width, and pulse frequency, to different VNS therapeutic setting that are less intense (down-titrate) or more intense (up-titrate).

Finally, using the “High Dose” input control 112 d, the patient 10 can trigger the neurostimulator 12 to initiate a higher duty cycle while maintaining the same intensity of VNS. For example, the duty cycle could be stepwise increased from 20% to 25%. Other manner of accommodating multiple stimulation operating modes or inhibition periods through use of the electromagnetic controller 110 are possible.

While the invention has been particularly shown and described as referenced to the embodiments thereof, those skilled in the art will understand that the foregoing and other changes in form and detail may be made therein without departing from the spirit and scope. 

1. A multi-modal vagus nerve neurostimulator for treating chronic cardiac dysfunction, comprising: an implantable neurostimulator comprising a pulse generator configured to deliver electrical therapeutic stimulation tuned to restore autonomic balance through continuously-cycling, intermittent and periodic electrical pulses simultaneously delivered at an intensity that avoids acute physiological side effects and with an unchanging cycle not triggered by physiological markers in a manner that results in creation and propagation (in both afferent and efferent directions) of action potentials within neuronal fibers comprising a cervical vagus nerve of a patient through a pair of helical electrodes via an electrically coupled nerve stimulation therapy lead; and an external electromagnetic controller configured to transmit a plurality of magnetic signals uniquely associated with operating modes stored in a recordable memory, the neurostimulator switching to the corresponding operating mode in response to the magnetic signals.
 2. A neurostimulator according to claim 1, further comprising: a patient-operable control comprised in the external electromagnetic controller, actuation of which enables separate selection of each of the operating modes and transmission of the magnetic signal corresponding to the operating mode selection.
 3. A neurostimulator according to claim 2, wherein the operating modes stored in the recordable memory comprise one or more of a high therapeutic dosage, therapy titration, therapy suspension, and sleep modes.
 4. A neurostimulator according to claim 2, further comprising: a patient feedback device comprised in the external electromagnetic controller, which outputs an indication of acceptance of the selected operating mode by the neurostimulator.
 5. A neurostimulator according to claim 1, wherein the electrical therapeutic stimulation is further defined to bi-directionally propagate through neuronal fibers in the cervical vagus nerve by first activating A-fibers of the cervical vagus nerve, then B-fibers of the cervical vagus nerve, and finally C-fibers of the cervical vagus nerve.
 6. A vagus nerve neurostimulator system with multiple patient-selectable modes for treating chronic cardiac dysfunction, comprising: an implantable neurostimulator comprising: a pulse generator coupled to a therapy lead terminated by a pair of helical electrodes positioned over a cervical vagus nerve of the patient, the pulse generator configured to deliver through the helical electrodes continuously-cycling, intermittent and periodic electrical stimulation that is parametrically defined to in both afferent and efferent directions create and propagate action potentials within neuronal fibers in the cervical vagus nerve; and a magnetic switch configured to switch the pulse generator between a plurality of operating modes stored in a recordable memory that are each separately selectable in response to a unique and remotely-applied magnetic signal; and an external controller comprising: patient-actuatable controls configured to enable selection of one of the operating modes stored in the recordable memory of the pulse generator; and an electromagnetic transmitter configured to output the magnetic signal uniquely associated with the operating mode as selected with the controls.
 7. A neurostimulator system according to claim 6, wherein the pulse generator is further configured to first activate A-fibers of the patient's cervical vagus nerve, then B-fibers of the patient's cervical vagus nerve, and finally C-fibers of the patient's cervical vagus nerve.
 8. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a sleep operating mode of the neurostimulator configured to temporarily inhibit or reduce stimulation for a fixed time period.
 9. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a suspend operating mode of the neurostimulator configured to completely suspend the electrical stimulation, the suspension comprising one of suspending the electrical stimulation all at once and suspending the electrical stimulation by gradually reducing levels of the electrical stimulation over one of over a fixed time period, amplitude-related time (fixed rate of decline) period or programmable time period.
 10. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a suspend operating mode of the neurostimulator configured to down-titrate the electrical stimulation in response to bradycardia by gradually reducing the electrical stimulation until the bradycardia is no longer present.
 11. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a titration mode configured to initiate a titration protocol on a periodic basis or when triggered.
 12. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a titration mode configured to automatically titrate on a schedule without intervention by the patient, the automatic titration comprising at least one of up-titration in response to a side-effect-free period of time and down-titration in response to a side effect.
 13. A neurostimulator system according to claim 6, wherein the operating modes stored in the recordable memory comprise a high dose mode configured to initiate a higher duty cycle of the electrical stimulation.
 14. A neurostimulator system according to claim 6, the patient-actuatable controls further comprising at least one of: one control per operating mode stored in the recordable memory, actuation of which causes the electromagnetic transmitter to transmit the magnetic signal uniquely associated with the one control; and a multi-modal control for a plurality of the operating modes stored in the recordable memory, actuation of which causes the electromagnetic transmitter to transmit the magnetic signal uniquely associated with the actuated mode of the multi-modal control.
 15. A neurostimulator system according to claim 6, the external controller further comprising: a patient feedback device configured to output to the patient an indication of acceptance of the selection by the neurostimulator.
 16. A neurostimulator system according to claim 6, wherein patient feedback device comprises at least one of: a speaker configured to provide at least one of audible and verbal feedback upon operation of the patient-actuatable controls; an indicator light configured to provide visual feedback upon operation of the patient-actuatable controls; a motion generator configured to provide tactile feedback upon operation of the patient-actuatable controls; and a display configured to provide at least one of alphanumeric and graphical feedback upon operation of the patient-actuatable controls.
 17. A neurostimulator system according to claim 16, the display further comprising: a touch-sensitive interface configured to either replace or supplement operation of the patient-actuatable controls.
 18. A vagus nerve neurostimulator system for treating chronic cardiac dysfunction with multiple remotely patient-selectable modes, comprising: a cervical vagus nerve stimulation therapy lead, comprising: a pair of helical electrodes configured to conform to an outer diameter of a cervical vagus nerve sheath of a patient; and a set of connector pins electrically connected to the helical electrodes by an insulated electrical lead body; and a neurostimulator powered by a primary battery and enclosed in a hermetically sealed housing, further comprising: an electrical receptacle comprised on an outer surface of the housing into which the connector pins are securely and electrically coupled; and a pulse generator configured to therapeutically stimulate the cervical vagus nerve through the helical electrodes by delivering continuously-cycling, intermittent and periodic electrical stimulation that is tuned in a manner that results in creation and propagation (in both afferent and efferent directions) of action potentials within neuronal fibers to both efferently activate the heart's intrinsic nervous system and afferently activate the patient's central reflexes by creating and propagating the action potentials; and a magnetic switch configured to switch the pulse generator between a plurality of operating modes stored in a recordable memory that are each separately selectable in response to a unique and remotely-applied magnetic signal, the operating modes comprising one or more of a high therapeutic dosage, therapy titration, therapy suspension, and sleep modes; and an external patient controller comprising: patient-actuatable controls configured to accept an input from a patient indication a selection of one of the pulse generator's operating modes stored in a recordable memory; an electromagnetic transmitter configured to output the magnetic signal uniquely associated with the selected operating mode; and a patient feedback device configured to output to the patient an indication of acceptance of the selection by the neurostimulator.
 19. A neurostimulator system according to claim 18, wherein the pulse generator is further defined to create and propagate the action potentials within the neuronal fibers in the cervical vagus nerve by first activating A-fibers of the patient's cervical vagus nerve, then B-fibers of the patient's cervical vagus nerve, and finally C-fibers of the patient's cervical vagus nerve.
 20. A neurostimulator system according to claim 18, wherein the operating modes stored in the recordable memory are parametrically defined through sets of parameters, comprising one or more of: a high dose mode parameters set configured to initiate a higher duty cycle of the electrical stimulation in response to selection by the patient of the high therapeutic dosage mode; a titration mode parameters set configured to at least one of initiate a titration protocol on a periodic basis or when triggered, and to automatically titrate on a schedule without intervention by the patient, the automatic titration comprising at least one of up-titration in response to a side-effect-free period of time and down-titration in response to a side effect; and a suspend operating mode parameters set configured to completely suspend the electrical stimulation, the suspension comprising one of suspending the electrical stimulation all at once and suspending the electrical stimulation by gradually reducing levels of the electrical stimulation over one of over a fixed time period, amplitude-related time (fixed rate of decline) period or programmable time period; a bradycardia suspend operating mode parameters set configured to down-titrate the electrical stimulation in response to bradycardia by gradually reducing the stimulation parameters until the bradycardia is no longer present; and a sleep operating mode parameters set configured to temporarily inhibit or reduce stimulation by the neurostimulator for a fixed time period in response to selection by the patient of the sleep mode. 